Abstract
| Original language | English |
|---|---|
| Article number | 2896 |
| Journal | Nature Communications |
| Volume | 9 |
| DOIs | |
| Publication status | Published - 2018 |
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Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens. / Escobar, G; Barbarossa, L; Barbiera, G; Norelli, M; Genua, M; Ranghetti, A; Plati, T; Camisa, B; Brombin, C; Cittaro, D; Annoni, A; Bondanza, A; Ostuni, R; Gentner, B; Naldini, L.
In: Nature Communications, Vol. 9, 2896, 2018.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens
AU - Escobar, G
AU - Barbarossa, L
AU - Barbiera, G
AU - Norelli, M
AU - Genua, M
AU - Ranghetti, A
AU - Plati, T
AU - Camisa, B
AU - Brombin, C
AU - Cittaro, D
AU - Annoni, A
AU - Bondanza, A
AU - Ostuni, R
AU - Gentner, B
AU - Naldini, L
PY - 2018
Y1 - 2018
N2 - Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. © 2018, The Author(s).
AB - Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. © 2018, The Author(s).
U2 - 10.1038/s41467-018-05315-0
DO - 10.1038/s41467-018-05315-0
M3 - Article
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2896
ER -